THE USE OF ANTIBODY TESTS FOR SARS-COV-2 IN THE CONTEXT OF DIGITAL GREEN CERTIFICATES
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TECHNICAL REPORT
The use of antibody tests for SARS-CoV-2 in
the context of Digital Green Certificates
10 May 2021
Key messages
• This brief technical note is to inform the discussion on using Digital Green Certificates to facilitate the safe
and free movement of citizens within the EU during the COVID-19 pandemic.
• At the moment, antibody tests are mostly used in researchi studies of the population rather than for
individual diagnosis of COVID-19 cases.
• A positive antibody test result can be proof of a past (including recent) infection, without providing any
indication of the time of infection, and cannot exclude a current ongoing infection. Therefore, is not an
absolute proof that a person is not infectious and/or protected against a new infection and cannot
transmit the virus further.
• Even if antibody tests provide some evidence of an immune responseii, it is not known if the antibody
levels offer sufficient protection or how long such protection would last, i.e. how long this part of a Digital
Green Certificate would be valid. It may well be that soon after a positive antibody test, the antibodies
become undetectable.
• It is still unknown whether the antibodies detected by commercial tests currently in use would prevent
infection with newly emerging SARS-CoV-2 variants.
• There are a variety of antibody testsiii and a comparison of their results is extremely difficult due to this
varietyiv and the lack of standardisation.
• The tests that target the spike protein will be unable to distinguish between people who have been
previously infected and those who have received at least one dose of the vaccine.
i
Sero-epidemiological studies.
ii
The presence of neutralising antibodies against SARS-CoV-2 provides the best current indication for protection against
reinfection for previously-infected individuals. Neutralising antibody tests (e.g. cPass) are now commercially available but are
not widely used and most tests just detect so-called binding antibodies.
iii
Qualitative or quantitative, detecting antibodies of different types (e.g. IgG, IgM), neutralising or binding, and against
different proteins (e.g. the spike protein or the nucleocapsid).
iv
According to the ‘COVID-19 Diagnostic Testing database’ of the Joint Research Centre, at the time of writing this document
there are 469 commercially available CE-marked antibody tests available in EU/EEA countries.
Suggested citation: European Centre for Disease Prevention and Control. The use of antibody tests for SARS-CoV-2 in the
context of Digital Green Certificates – 20 May 2021. ECDC: Stockholm; 2021.
© European Centre for Disease Prevention and Control. Stockholm, 2021.TECHNICAL REPORT Use of antibody tests for SARS-CoV-2 in the context of Digital Green Certificates
Introduction
This brief technical note was developed at the request of the European Commission to inform the discussion on
Digital Green Certificates to facilitate the safe and free movement of citizens within the EU during the COVID-19
pandemici.
Antibodies are generated as part of the individual's immune response against SARS-CoV-2 infection, or in
response to vaccination, and indicate previous (including recent) infection or vaccination. Serological tests are
developed to detect different types of antibodies:
• IgM antibodies are early antibodies and can provide the first indication of an immune response against
SARS-CoV-2 infection. These antibodies are not as specific and generally not as long-lasting as IgG
antibodies (see below), so interpreting their significance requires clinical experience.
• IgG antibodies are specific to the different antigens of the virus. So far, study results suggest that these
antibodies can be reliably detected starting 14 days after SARS-CoV-2 infection or after vaccination.
Currently, serology tests are used in sero-epidemiological studies to monitor the prevalence of SARS-CoV-2 in
different population groups and areas. Such sero-epidemiological studies are performed in EU/EEA countries and
the sero-epidemiological study network in the WHO European Region is coordinated jointly by the WHO Regional
Office for Europe and ECDC. Studies are ongoing, but results are not yet available.
The situation and knowledge about immunity against SARS-CoV-2 is evolving rapidly. This technical note is based
on current knowledge and will be re-assessed when new information becomes available.
Considerations for the use of antibody tests
for issuing Digital Green Certificates
What do antibody tests tell us about a SARS-CoV-2
infection?
• Antibodies persist for at least six months, with the rate of decline varying according to factors such as age
and severity of the previous COVID-19 infection. They also appear to be associated with some level of
protection from reinfection. Studies with longer follow-up periods are ongoing. The relationship between
antibodies in response to infection and immunity to infection with SARS-CoV-2 is under investigation, but
not fully understood, e.g. some mild or asymptomatic COVID-19 cases do not develop detectable anti-
SARS-CoV-2 antibodies following a laboratory PCR-confirmed infection.
• Serological tests target specific SARS-CoV-2-induced antibodies. However, results only provide a partial
picture of the immune response against the virus since T-cell mediated responses are not considered. The
induction of SARS-CoV-2-specific memory T-cells is also important for long-term protection and play a
vital role in virus clearance. T-cells may be maintained even if there are not measurable levels of serum
antibodies. This further complicates the assessment of the existence and duration of immunity based on
antibodies only. Individuals may also have varying immune responses to infection.
• While serological assays play an important role in research and sero-epidemiological investigations, they
are not recommended for the diagnosis of an acute SARS-CoV-2 infection. Available antibody tests
measure the presence or absence of IgM and IgG against SARS-CoV-2. The level of IgM antibodies begin
to rise one week after the initial infection, while IgG antibodies appear later than IgM (usually within 14
days after infection); they only provide evidence of a past (including recent) infection. Antibody tests do
not detect the virus itself and cannot be used to identify people with an acute viral infection or assess the
level of infectiousness of the person, and will therefore not contribute to preventing virus transmission
from an acute case.
• Antibody tests cannot determine the exact time of infection if it is unknown (i.e. no confirmation through
a positive PCR or antigen test).
i
https://ec.europa.eu/info/live-work-travel-eu/coronavirus-response/safe-covid-19-vaccines-europeans/covid-19-digital-green-
certificates_en
2TECHNICAL REPORT Use of antibody tests for SARS-CoV-2 in the context of Digital Green Certificates
• The detection of antibodies in a serological test may provide evidence of a past infection. However, there
is uncertainty regarding how well, and at what level, the presence of IgM and IgG antibodies has a
neutralising effect on the virus and how long this lasts. The relationship between antibody levels and
clinical response is yet to be fully determined. Therefore, when the time of infection is unknown, a certain
antibody level cannot be directly correlated to protection through neutralising capacity of these antibodies
against SARS-CoV-2.
• It is unknown how well antibodies against previous SARS-CoV-2 lineages or variant viruses may protect
against newly emerging variants. Reinfection after a first COVID-19 episode remains a rare event.
However, there is a lack of data related to the emergence of new variants with different antigenic
properties and there are uncertainties regarding the duration of protection from reinfection conferred by
natural immunity. For example, it seems that people who have antibodies against older variants of the
virus are not fully protected against the B.1.351 variant virus originally detected in South Africa.
• People who are vaccinated with one dose of a COVID-19 vaccine may already elicit a strong immune
response and therefore test positive in the antibody test. Tests that identify antibodies to the spike
protein of the SARS-CoV-2 virus will be unable to distinguish between people who have been infected
previously and those who have received at least one dose of the vaccine.
Interpretation of antibody test results for diagnosis of
COVID-19
• Serological tests are not appropriate for diagnosing an acute SARS-CoV-2 infection. Since antibodies
(IgM/IgG) against the virus are detectable from day seven after the onset of symptoms, a negative
serology result during the first seven days of illness cannot be used to rule out infection. Although the
sensitivity of antibody detection increases after day seven, a negative serology result after day seven
should be carefully interpreted before ruling out a case. On the other hand, a positive result between
days 7-14 indicates a previous infection and cannot rule out the presence of the virus. For these reasons,
serology alone should not be used to rule out an ongoing infection. Likewise, a patient with respiratory
symptoms and a positive antibody tests, does not necessarily have an ongoing SARS-CoV-2 infection. It
should also be noted that the sensitivity of serological testing in elderly or immuno-compromised people is
unknown. This is because their age or condition can have an impact on the individual immune response.
For these reasons, results from antibody tests should be interpreted with caution.
• For the purpose of Digital Green Certificates, a positive serum antibody test does not confirm if an
individual is non-infectious and cannot transmit the virus. Antibody tests cannot replace RT-PCR or rapid
antigen tests as the purpose and target are different (antibody vs. direct detection of virus genome or
viral protein). Regarding the potential timing for conducting such tests for Digital Green Certificates, it
should be noted that recent antibody tests (i.e. one to two weeks before travel) are unable to exclude the
possibility of an active infection.
Considerations regarding available antibody tests
• Antibody tests currently used in Member States are not harmonised/standardised and results are not
comparable. Laboratory methods used by Member States target different antibodies (IgM and/or IgG) and
different epitopes of SARS-CoV-2, which makes comparison of results challenging. While a wide range of
SARS-CoV-2 proteins are targeted in the different available antibody tests, only anti-spike and anti-
receptor binding domain (RBD) IgG antibodies correlate well with neutralising antibodies, which is the
best current proxy for protection against reinfection and therefore transmission.
• According to the ‘COVID-19 Diagnostic Testing database’ of the Joint Research Centre the list of all CE-
marked antibody assays available in the EU/EEA, as of 10 May, includes 469 tests. Limited clinical
validation data are available for these tests. The US Food and Drug Administration agency publishes a list
of independent validations here. However, sensitivity and specificity estimates shown may not be
indicative of the real-life performance of the tests. The sample type collected for each test (e.g. plasma,
serum or whole blood, including finger stick blood) may affect the test results and their comparability to
each other.
• WHO has developed an international standard to harmonise and standardise the different serological
assays for detection of neutralising antibodies. The Joint Research Centre has also developed similar
standards. These standards can serve as the basis for the calibration of tests that quantify antibodies.
Calibration will need to be performed at individual laboratories that are using the different commercial
antibody tests.
3TECHNICAL REPORT Use of antibody tests for SARS-CoV-2 in the context of Digital Green Certificates
• Antibody tests are qualitative and are useful from a population, rather than an individual, perspective.
Quantitative detection kits using ELISA are primarily used for research purposes, but the comparability
between laboratories is hindered by the lack of available reference material, including the material and
systems based on newly-emerging variants. Most commercially available detection reagents used for rapid
detection of antibodies (lateral-flow based rapid antibody assays) or large-scale automatic immunoassays
only provide qualitative results (i.e. presence or absence of antibodies). Neutralising antibody tests that
allow for the rapid detection of total neutralising antibodies in a sample by mimicking the interaction
between the virus and the host cell (e.g. cPass) are now commercially available but not widely in use. As
with other serological tests, even a positive neutralising antibody test does not guarantee protection
against reinfection or the durability of neutralising antibody levels.
• There is evidence that in areas of low prevalence, the positive predictive value of antibody tests can be
very low, meaning that there is a high risk that positive results would be false. However, the individual
likelihood of a positive antibody test is dependent on the individual exposure and likelihood of infection
over time, and it is challenging to estimate this for different populations across EU/EEA countries who
have faced different epidemiological situations since the introduction of SARS-CoV-2i. In the context of
potential co-circulation of other seasonal coronaviruses with SARS-CoV-2, the specificity of some antibody
tests may decrease and thereby the risk of false positive tests may increase.
Antibody tests in the context of public health measures
• It is possible that individuals with certificates issued on the basis of a positive serology may be falsely
reassured that they can relax attitudes towards behaviours that are essential to limiting risk of infection
and onwards transmission, such as physical distancing, mask use and hand washing. As mentioned
above, whilst positive serology result may be suggestive of prior infection, it may not guarantee
protection from reinfection, or to newly-emerging variants with possible immune-escape potential.
• Any implementation of certificates on the basis of positive serology should be carefully considered and be
accompanied by strong public messages and relevant communication about the importance of both
vaccination and public health measures to reduce SARS-CoV-2 transmission.
Contributing ECDC experts (alphabetical
order):
Cornelia Adlhoch, Agoritsa Baka, Piotr Kramarz, Annette Kraus, Angeliki Melidou, Ajibola Omokanye
i
https://www.nature.com/articles/s41598-021-84173-1
4TECHNICAL REPORT Use of antibody tests for SARS-CoV-2 in the context of Digital Green Certificates
Bibliography
World Health Organization, Scientific Brief ‘Immunity passports’ in the context of COVID-19. WHO; April 2020.
Available at: https://www.who.int/news-room/commentaries/detail/immunity-passports-in-the-context-of-covid-
19
European Centre of Disease Prevention and Control. Interim guidance on the benefits of full vaccination against
COVID-19 for transmission and implications for non-pharmaceutical interventions. ECDC; Stockholm; 2021.
Available at: https://www.ecdc.europa.eu/sites/default/files/documents/Interim-guidance-benefits-of-full-
vaccination-against-COVID-19-for-transmission-and-implications-for-non-pharmaceutical-interventions.pdf
European Centre of Disease Prevention and Control. Risk of SARS-CoV-2 transmission from newly-infected
individuals with documented previous infection or vaccination. ECDC; Stockholm; 2021. Available at:
https://www.ecdc.europa.eu/en/publications-data/sars-cov-2-transmission-newly-infected-individuals-previous-
infection
European Centre of Disease Prevention and Control. Immune responses and immunity to SARS-CoV-2. ECDC;
Stockholm; 2021. Available at: https://www.ecdc.europa.eu/en/covid-19/latest-evidence/immune-responses
European Centre of Disease Prevention and Control. Risk of transmission after vaccination. ECDC; Stockholm;
2021. Available at: https://www.ecdc.europa.eu/sites/default/files/documents/Risk-of-transmission-and-
reinfection-of-SARS-CoV-2-following-vaccination.pdf
Brownstein, N.C., Chen, Y.A. Predictive values, uncertainty, and interpretation of serology tests for the novel
coronavirus. Sci Rep 11, 5491 (2021). https://doi.org/10.1038/s41598-021-84173-1. Available at:
https://www.nature.com/articles/s41598-021-84173-1
Centres for Disease Control and Prevention. Interim Guidelines for COVID-19 Antibody Testing. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html
European Commission, Joint Research Centre - COVID-19 In Vitro Diagnostic Devices and Test Methods
Database. Available at: https://covid-19-diagnostics.jrc.ec.europa.eu/
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